Routine clinical evaluation of osteoporosis (OP) has been limited to the assessment of bone mineral density (BMD) using dual energy X-ray absorptiometry (DEXA) and/or CT. The majority of bone, the organic matrix and water, which together represent ~57% of bone by volume, are not accessible with these techniques. BMD alone predicts fractures with only a 30-50% success rate. The missing factor may be the contribution of bone organic matrix and water. Bone water occurs at various locations and in different states. It is bound to the organic matrix or in 'free' form in the Haversian and the lacunar-canalicular systems. The bound water content reflects organic matrix density. The free water content can potentially provide a surrogate measure of bone porosity. However, neither DEXA nor CT can detect either bound or free water in cortical bone. We have developed Ultrashort Time-to-Echo (UTE) magnetic resonance imaging (MRI) sequences with minimum TEs of 8 s, and this makes it possible to detect water signal from bone. Total bone water can be quantified by comparing UTE signal from bone and a water phantom. Bound water can be selectively imaged with SIR-UTE sequences which use a single adiabatic inversion pulse to invert and null the free water magnetization. Free water can be selectively imaged with DIR-UTE sequences which saturate bound water while leave free water magnetization unaffected. Bound water has ~10 times shorter T2* than free water. The two components may be separated with bi-component fitting. Free water has a short T2* but long T2, and may be imaged with FSE sequences. The UTE approach may detect the effect of Gadolinium chelates within cortical bone and study its perfusion at high resolution. This provides a new way to characterize cortical bone. In this proposal we hypothesize that bone water content and bone perfusion can be non-invasively assessed by novel MRI techniques, and can serve as sensitive biomarkers of bone quality. We aim to develop novel UTE, SIR-UTE, DIR-UTE and FSE techniques to measure total, bound and free water in cortical bone (Aim 1), to evaluate the accuracy of MR measures of two groups of women cadaveric human tibia specimens, the younger group (< 60 years old) and the older group (> 80 years old), and correlate the results with cortical porosity determined by mCT and organic matrix content determined by ashing, as well as elastic properties (modulus, yield stress and strain) and failure properties (ultimate stress, failure strain and energy) determined by 4-point bending test (Aim 2), and to develop translational MR techniques to quantify total, bound and free water as well as bone perfusion in two groups of postmenopausal women: i.e., below 60 without OP and above 80 with OP (Aim 3). The intention is to develop and validate these techniques in tissue studies and a small number of patients to provide preliminary data for an RO1 grant application on the use of MR in diffuse bone disease including OP, renal osteodystrophy, paget disease and osteomalacia. The comprehensive characterization of bone in these conditions could have a profound impact in their diagnosis and treatment.